Process optimization for the synthesis of the key intermediate mebroclopipe dihydrochloride (1-[2-(4-bromo-2-chloro-3-methylphenoxy)ethyl]-4-methylpiperazine dihydrochloride)

Initial Route

• Low yielding
• Large amounts of starting materials
• Severe issue with the lack of selectivity for the methylation step
• Mitsunobu reaction
• Four steps
• One cryogenic step

Optimized Route

• Starts from a cheaper starting material
• Pd catalyzed hydroxylation
• Uses DABCO in an efficient and elegant method for introducing the piperazine chain (replacing the
• Mitsunobu reaction)
  Simple, scalable and safe to operate
• Three steps, all telescoped
• High yield
• Crystallize the final product as a hydrochloride salt

Sygnature Discovery conducted process optimization for the synthesis of 1-[2-(4-bromo-2-chloro-3-methylphenoxy)ethyl]-4-methylpiperazine dihydrochloride, a pivotal intermediate referenced in WO 2020/078875 A1. Efficient access to this molecule was essential to ensure reliable supply for further preclinical and clinical studies.

The initial synthetic route was characterized by significant inefficiencies, comprising four steps with an overall yield of only 27% (72% average yield per step). Key drawbacks included the use of expensive starting materials, challenging regioselectivity issues, a problematic Mitsunobu reaction, and the necessity of a cryogenic step, which collectively hindered scalability and practical GMP manufacturing.

By harnessing our deep expertise in synthetic route optimization, Sygnature Discovery dramatically improved the process, developing a concise and robust three-step telescoped synthesis. This optimized route features an innovative palladium-catalyzed hydroxylation and an elegant, highly efficient DABCO ring-opening reaction for the introduction of the piperazine chain, effectively replacing the problematic Mitsunobu step.

The enhanced process demonstrated a substantial increase in yield, achieving an impressive 73% overall yield (90% average yield per step). It also employed readily available, cost-effective starting materials and featured an excellent impurity control strategy, enabling final purification through straightforward crystallization of the hydrochloride salt, further enhancing scalability, safety, and GMP compliance.

This successful optimization clearly exemplifies Sygnature Discovery’s capability to innovate synthetic methodologies, providing streamlined, scalable solutions tailored for seamless technology transfer and robust progression from preclinical to clinical phases.